Revision Year: 2014 Publisher: GUERBET, BP 57400 F-95943 Roissy CDG Cedex, France Manufacturing site address: GUERBET, 16-24 rue Jean Chaptal, 93600 Aulnay-sous-Bois, France
a) Administration via certain specific routes (articular, intra-uterine, etc.) results in varying degrees of systemic diffusion, i.e. systemic effects may be observed.
b) However, the allergic immune mechanism is not dose-dependent and immuno-allergic reactions may occur at any time, regardless of the administration route.
In the absence of specific studies, myelography is not an indication for Xenetix. All iodinated contrast agents can cause minor or major reactions that can be life-threatening. They may occur immediately (within 60 minutes) or be delayed (up to 7 days). They are often unpredictable.
Because of the risk of major reactions, emergency resuscitation equipment should be available for immediate use.
Several mechanisms have been evoked to explain the occurrence of these reactions:
Patients who have already experienced a reaction during administration of an iodinated contrast agent are at higher risk of experiencing another reaction following administration of the same or possibly a different iodinated contrast agent, and are thus considered to be at-risk patients.
Before administering an iodinated contrast agent, it is important to ensure that the patient is not scheduled to undergo a scintigraphic examination or laboratory tests related to the thyroid or to receive radioactive iodine for therapeutic purposes.
Administration of contrast agents via any route disrupts thyroid hormone concentrations and iodine uptake by the thyroid or by metastases of thyroid cancer, until urine iodine levels have returned to normal.
Extravasation is an uncommon complication (0.04% to 0.9%) of intravenous injections of contrast media. More frequent with the high osmolar products, most of the injuries are minor, however severe injuries such as skin ulceration, tissue necrosis, and compartment syndrome may occur with any iodinated contrast medium. The risk and/or severity factors are patient-related (poor or fragile vascular conditions), and technique-related (use of a power injector, large volume). It is important to identify these factors, optimize the injection site and technique accordingly, and monitor the injection prior to, during and after the injection of Xenetix.
Prior to the examination:
Corticosteroids and H1-type antihistamines have been suggested as premedication in patients presenting with the highest risk for intolerance reactions (history of intolerance to an iodinated contrast agent). However, they do not prevent the occurrence of serious or fatal anaphylactic shock. During the procedure, the following measures must be maintained:
After the examination:
Iodinated contrast agents can induce a transient alteration in renal function or worsen pre-existing renal insufficiency. Preventive measures include:
Iodinated contrast agents can be used in haemodialysed patients as the agents are removed by dialysis. Prior approval should be obtained from the haemodialysis department. Adequate hydration should be ensured in all patients before and after contrast media administration and particularly in patients with renal impairment or diabetes where it is important to maintain hydration to minimise deterioration in renal function.
Particular attention is required when a patient presents with both hepatic and renal insufficiency since, in this situation, the risk of contrast agent retention is increased.
Care should be taken in case of renal or hepatic impairment, diabetes or in patients with sickle cell disease.
Stabilisation of asthma is recommended before the injection of an iodinated contrast agent. Due to an increased risk of bronchospasm, special caution should be taken in patients who suffered an asthmatic attack within eight days prior to the examination.
After iodinated contrast agent injection, particularly in patients with a goitre or a history of dysthyroidism, there is a risk either of a flare-up of hyperthyroidism or development of hypothyroidism. There is also a risk of hypothyroidism in neonates who have received, or whose mother has received, an iodinated contrast agent.
In patients with cardiovascular disease (such as early or patent heart failure, coronaropathy, pulmonary hypertension, valvulopathy, cardiac arrhythmias), the risk of cardiovascular reactions is increased after administration of an iodinated contrast agent. Intravascular injection of the contrast medium may cause pulmonary oedema in patients with manifest or incipient heart failure, whereas administration in pulmonary hypertension and heart valve disorders may result in marked changes in haemodynamics. The frequency and degree of severity appear related to the severity of the cardiac disorders. In case of severe and chronic hypertension, the risk of renal damage due to administration of the contrast medium and also due to the catheterisation itself may be increased. Careful weighing up of the risk-benefit ratio is necessary in these patients.
The benefit-to-risk ratio must be evaluated for each case:
Patients with phaeochromocytoma may develop a hypertensive crisis after intravascular administration of a contrast agent, and must be monitored prior to the examination.
Administration of a contrast agent may worsen the symptoms of myasthenia gravis.
Adverse reactions related to iodinated contrast agent administration may be intensified in patients showing pronounced agitation, anxiety and pain. Appropriate management such as sedation may be necessary.
This medicinal product contains sodium. It contains less than 1 mmol sodium per 100 mL, i.e. essentially “sodium-free”.
Pregnancy for hysterosalpingography.
In the interview and with appropriate tests, systematically check for possible pregnancy in women of childbearing age. Exposure of the female genital routes to x-rays must be subject to careful evaluation of the benefit-to-risk ratio.
In the event of inflammation or acute pelvic infection, hysterosalpingography can only be performed after a careful assessment of the benefit-to-risk ratio.
(see Section 4.4.1.2.2. Precautions for use – renal insufficiency).
Iodinated contrast agents alter the uptake of radioactive iodine by the thyroid for several weeks, which may on the one hand result in diminished uptake in thyroid scintigraphy and on the other hand decrease the efficacy of iodine 131 treatment. In patients scheduled to undergo renal scintigraphy with injection of Page 7 of 11 a radiopharmaceutical excreted by the renal tubules, it is preferable to carry out this examination before injecting the iodinated contrast agent.
These medicinal products reduce the efficacy of the cardiovascular compensation mechanisms that occur in haemodynamic disorders. The physician must be aware of this before injecting the iodinated contrast agent and appropriate intensive care equipment must be available.
Due to the risk of dehydration provoked by diuretics, rehydration with water and electrolytes must be carried out prior to the examination in order to limit the risk of acute renal failure.
The risk of developing a reaction to the contrast agents is increased if the patient has recently been treated with interleukin 2 (intravenous route), i.e. rash or, more rarely, hypotension, oliguria, or even renal failure.
High concentrations of iodinated contrast agents in plasma and urine may interfere with the in vitro determination of bilirubin, proteins and inorganic substances (iron, copper, calcium and phosphate). It is recommended that these determinations should not be carried out within 24 hours following the examination.
In the interview and with appropriate tests, systemically check for possible pregnancy in women of childbearing age. Exposure of the female genital routes to x-rays must be subjected to careful evaluation of the benefit-to-risk ratio.
Hysterosalpingography with Xenetix 300 during pregnancy is contraindicated.
Animal studies have not shown any teratogenic effects.
In the absence of any teratogenic effects in animal species, no malformative effect is expected in humans. To date, substances causing malformations in humans have always proved to be teratogenic in animals during studies properly conducted in two species.
The transient iodine overload following administration to the mother may induce foetal dysthyroidism if the examination takes place after more than 14 weeks of amenorrhoea. However, in view of the reversibility of the effect and expected benefit to the mother, the isolated administration of an iodinated contrast agent is justifiable if the indication for the radiological examination in a pregnant woman has been carefully evaluated.
The product was not found to be mutagenic under the test conditions used. No data on reproductive function are available.
Iodinated contrast agents are only excreted in breast milk in very small amounts. Isolated administration to the mother consequently involves a minor risk of adverse reactions in the infant. It is advisable to stop breastfeeding for 24 hours after administration of the iodinated contrast agent.
No particular risks are known.
During clinical studies on 905 patients, 11% of patients experienced an adverse reaction related to administration of Xenetix (apart from feeling of warmth), the most common being pain, injection site pain, bad taste and nausea.
Undesirable effects related to the use of Xenetix are generally mild to moderate, and transient.
The adverse reactions most commonly reported during administration of Xenetix since marketing are feeling of warmth, and pain and oedema at the injection site.
The hypersensitivity reactions are usually immediate (during the injection or over the hour following the start of the injection) or sometimes delayed (one hour to several days after the injection), and then appear in the form of adverse skin reactions.
Immediate reactions comprise one or several, successive or concomitant effects, usually including skin reactions, respiratory and/or cardiovascular disorders, which may be the first signs of shock, which can rarely be fatal.
Severe rhythm disorders including ventricular fibrillation have been very rarely reported in heart disease patients, in as well as out of a context of hypersensitivity (see Section 4.4. Special warnings and special precautions of use)
The adverse reactions are listed in the table below by SOC (System Organ Class) and by frequency with the following guidelines: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000), not known (cannot be estimated from the available data). The frequencies presented are derived from the data of an observational study on 352,255 patients.
Rare: hypersensitivity
Very rare: anaphylactoid reaction, anaphylactic reaction
Very rare: thyroid disorder
Rare: presyncope (vasovagal reaction), tremor*, paresthesia*
Very rare: coma*, convulsions*, confusion*, visual disorders*, amnesia*, photophobia*, transient blindness*, somnolence*, agitation*, headache
Rare: vertigo
Very rare: hearing impaired
Rare: tachycardia
Very rare: cardiac arrest, myocardial infarction (more frequent after intracoronary injection), arrhythmia, ventricular fibrillation, angina pectoris
Rare: hypotension
Very rare: circulatory collapse
Rare: dyspnoea, cough, tightness in the throat, sneezing
Very rare: respiratory arrest, pulmonary oedema, bronchospasm, laryngospasm, laryngeal oedema
Unknown: rhinitis
Uncommon: nausea
Rare: vomiting
Very rare: abdominal pain
Rare: angioedema, urticaria (localised or extensive), erythema, pruritus
Very rare: Acute Generalised Exanthematous Pustulosis, StevensJohnson syndrome, Lyell’s syndrome, eczema, maculopapulous exanthema (all as delayed hypersensitivity reactions)
Very rare: acute renal failure, anuria
Uncommon: feeling hot
Rare: facial oedema, malaise, chills, injection site pain
Very rare: injection site necrosis following extravasation, injection site oedema, injection site inflammation following extravasation
Very rare: blood creatinine increased
* Examinations during which the iodinated contrast agent concentration in arterial blood is high
The following adverse reactions were reported for other water-soluble iodinated contrast agents:
Nervous system disorders: Paralysis, paresis, hallucinations, speech disorders
Gastrointestinal disorders: Abdominal pain, diarrhoea, parotid gland enlargement, salivary hypersecretion, dysgeusia
Skin and subcutaneous tissue disorders: Erythema multiforme
Vascular disorders: Thrombophlebitis
Investigations: Electroencephalogram abnormal, blood amylase increased
Cardiovascular collapse of variable severity may occur immediately with no warning signs, or may complicate the cardiovascular manifestations mentioned in the above table.
Local pain and oedema may occur at the injection site without extravasation of the injected product and are benign and transient.
During intra-arterial administration, the sensation of pain at the injection site depends on the osmolality of the product injected.
Arthrography: arthralgias were frequently reported during clinical studies (4%).
Hysterosalpingography: pelvic pain was frequently reported during clinical studies (3%).
In the absence of incompatibility studies, this medicinal product must not be mixed with other medicinal products.
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